It has been reported by Davies, H., et al., Nature (2002) 417:949-954 that BRAF somatic missense mutations occur in 66% of malignant melanomas as well as at lower frequencies in other cancers. The mutations are in the kinase domain and a single substitution (V599E, now corrected to V600E) accounts for 80% of these mutations. These mutations result in proteins that have increased kinase activity. As these mutations are associated with malignant melanoma, inhibitors of the BRAF kinase proteins resulting from the V600E mutation have been employed as chemotherapeutic agents. Among these is Plexxikon 4032 (PLX-4032), also known as RG7204 and as Zelboraf®. In one study, this inhibitor produced a 70% response rate in metastatic melanoma for patients with the mutation, but generally does not produce durable responses. That is, the patients become resistant to this inhibitor.
To date, there appear to be no treatments available that overcome the resistance acquired by these patients to the inhibitors of kinase activity in BRAF kinase protein.
Inhibitors of receptor tyrosine kinases, in general, have been used as therapeutic agents for treating cancers. For example, U.S. Pat. No. 6,573,293 describes and claims the use of such inhibitors, including the drug marketed as Sutent® for the treatment of cancers including melanoma. Similar compounds are also claimed as useful in treating gastrointestinal stromal tumors and allergy-associated conditions in U.S. Pat. No. 7,211,600.
Sutent® itself, which is the maleate salt of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide is described and claimed in U.S. Pat. No. 7,125,905. Another such available drug is Nexavar® described and claimed in U.S. Pat. No. 7,235,576.
Applicants are aware of no suggestion in the art that these compounds are specifically effective in treating patients who have acquired resistance to BRAF mutant kinase inhibitors.